The invention relates to reducing hair growth in mammals, particularly for cosmetic purposes.
A main function of mammalian hair is to provide environmental protection. However, that function has largely been lost in humans, in whom hair is kept or removed from various parts of the body essentially for cosmetic reasons. For example, it is generally preferred to have hair on the scalp but not on the face.
Various procedures have been employed to remove unwanted hair, including shaving, electrolysis, depilatory creams or lotions, waxing, plucking, and therapeutic antiandrogens. These conventional procedures generally have drawbacks associated with them. Shaving, for instance, can cause nicks and cuts, and can leave a perception of an increase in the rate of hair regrowth. Shaving also can leave an undesirable stubble. Electrolysis, on the other hand, can keep a treated area free of hair for prolonged periods of time, but can be expensive, painful, and sometimes leaves scarring. Depilatory creams, though very effective, typically are not recommended for frequent use due to their high irritancy potential. Waxing and plucking can cause pain, discomfort, and poor removal of short hair. Finally, antiandrogens—which have been used to treat female hirsutism—can have unwanted side effects.
It has previously been disclosed that the rate and character of hair growth can be altered by applying to the skin inhibitors of certain enzymes. These inhibitors include inhibitors of 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase. See, for example, Breuer et al., U.S. Pat. No. 4,885,289; Shander, U.S. Pat. No. 4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007; Ahluwalia et al., U.S. Pat. No. 5,096,911; and Shander et al., U.S. Pat. No. 5,132,293.
Farnesoid X receptor (also known as “FXR”, “RIP14”, “bile acid receptor”, “BAR”, “HRR1” and “NR1H4”) is a member of the family of ligand-activated transcription factors that bind to specific cis-acting regulatory elements in the promoters of their target genes and modulate gene expression in response to ligands. Some of these receptors bind to their target genes as dimers consisting of two molecules of the same receptor (homodimers), while others bind to as dimers consisting of one molecule each of two different receptors (heterodimers). Famesoid X receptor forms a heterodimer with the retinoid X receptor (RXR) and binds to an inverted hexanucleotides repeat spaced by one nucleotide in the promoters of its target genes. Famesoid X receptor is activated through interaction with ligands such as farnesoids and bile acids. In addition, coactivators (DRIP205/TRAP220, SRC-1 and PGC-1 alpha) that bridge between the ligand-activated farnesoid X receptors and the basal transcription machinery, and/or influence the chromatin structure, can enhance the transcriptional activity of famesoid X receptor.
Farnesoid X receptor helps maintain bile acid homeostasis by modulating the expression of genes involved in the synthesis and transport of bile acid. Bile acids are the end product of cholesterol catabolism. Synthesis of bile acid is the predominant mechanisms for the excretion of excess cholesterol. Most bile acids in human are chenodeoxycholic acid, cholic acid, deoxycholic acid, ursodeoxycholic acid and lithocholic acid. While the level of bile acids is increased, famesoid X receptor is activated and upregulates the expression of the bile salt export pump that is responsible for bile acid excretion. In addition to bile acid excretion, bile acid-activated farnesoid X receptor represses the transcription of cholesterol 7alpha-hydroxylase (CYP7A1), which the rate-limiting enzyme in the bile acid biosynthesis pathway.